title: Association of early interferon-gamma production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children.
abstract: BACKGROUND
  Elucidating the cellular and molecular basis of naturally acquired immunity to Plasmodium falciparum infection would assist in developing a rationally based malaria vaccine. Innate, intermediate, and adaptive immune mechanisms are all likely to contribute to immunity. Interferon-gamma (IFN-gamma) has been implicated in both protection against and the pathogenesis of malaria in humans. In addition, considerable heterogeneity exists among rapid IFN-gamma responses to P. falciparum in malaria-naive donors. The question remains whether similar heterogeneity is observed in malaria-exposed individuals and whether high, medium, or low IFN-gamma responsiveness is differentially associated with protective immunity or morbidity.
  
  
  METHODS
  A 6-month longitudinal cohort study involving 206 school-aged Papua New Guinean children was performed. Peripheral blood mononuclear cells collected at baseline were exposed to live P. falciparum-infected erythrocytes. Early IFN-gamma responses were measured, and IFN-gamma-expressing cells were characterized by flow cytometry. IFN-gamma responsiveness was then tested for associations with parasitological and clinical outcome variables.
  
  
  RESULTS
  Malaria-specific heterogeneity in early IFN-gamma responsiveness was observed among children. High-level early IFN-gamma responses were associated with protection from high-density and clinical P. falciparum infections. Parasite-induced early IFN-gamma was predominantly derived from gammadelta T cells (68% of which expressed the natural killer marker CD56) and alphabeta T cells, whereas natural killer cells and other cells made only minor contributions. The expression of CD56 in malaria-responsive, IFN-gamma-expressing gammadelta T cells correlated with IFN-gamma responsiveness.
  
  
  CONCLUSIONS
  High, early IFN-gamma production by live parasite-stimulated peripheral blood mononuclear cells is a correlate of immunity to symptomatic malaria in Papua New Guinean children, and natural killer-like gammadelta T cells may contribute to protection.
authors.affiliation: Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Marthe C
authors.initials: MC
authors.lastname: D'Ombrain
authors.forename: Leanne J
authors.initials: LJ
authors.lastname: Robinson
authors.forename: Danielle I
authors.initials: DI
authors.lastname: Stanisic
authors.forename: Jack
authors.initials: J
authors.lastname: Taraika
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bernard
authors.forename: Pascal
authors.initials: P
authors.lastname: Michon
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Louis
authors.initials: L
authors.lastname: Schofield
mesh_terms: D000293:Adolescent; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008137:Longitudinal Studies; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000503:physiopathology; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000276:immunology*; D013223:Statistics as Topic; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D007371:Interferon-gamma